The seemingly limitless ability of influenza viruses to evade natural immunity has motivated research on vaccination strategies, but the impact of this work is limited by uncertainty about the nature of acquired immunity. Recent methodological advances have revealed that antibody-mediated immunity to influenza is surprisingly diverse. There is growing evidence that not only the order of exposure to antigens-from both vaccines and natural infection-but also the timing of these exposures may profoundly shape evolving antibody repertoires. Because the antibody response is central to protection from influenza infection and viral fitness, understanding the evolution of antibody repertoires has important consequences for clinical medicine and public health. The research proposed here combines observations from multiple fields to investigate how these repertoires evolve and shape the global epidemiology of influenza. We will test a set of related hypotheses that have significant implications for influenza's dynamics and vaccination strategies. In the proposed model, immunity from current and previous infections can compete with new responses, potentially biasing the antibody repertoire and changing disease risk. The work will proceed in two phases. In the first phase, we will use a computational model fitted to immunological data to evaluate the ability of interference between old and new responses to explain patterns of immunity by age and the ways in which infections and vaccines affect the risk of infection with related strains. We will also derive the optimal timing and breadth of vaccines to maximize individual protection in the absence of certainty about past and future exposures. In the second phase, we will expand the model to include transmission dynamics and viral evolution. We will test whether competition between new and preexisting responses can explain age-specific rates of infection and rates of antigenic evolution. Optimal vaccination strategies for populations will be inferred assuming vaccine-imposed selective pressure and the possibility of escape mutations. The successful completion of these experiments will test the validity of current hypotheses of antibody repertoire evolution, evaluate the impact of within-host immune evolution on dynamics at larger scales, and provide a theoretical foundation for vaccination strategies against a complex, evolving pathogen. 1